Piperazino derivatives and methods for their manufacture



nited States Patent 2,985,654 1 PIPERAZINO DERIVATIVES AND METHODS'FOR THEIR MANUFACTURE Margaret H. Sherlock and Nathan Sperben Bloor nfield, N.J., assiguors to Schering Corporation, Bloomfield, N .J., a corporation of New Jersey H No Drawing. Filed Sept. 21, 1956, Seniflo.

13 Claims. (Cl. 260-243) This invention relates to a new groupof chemical compounds which possess important therapeutic properties and wherein Y is a bivalent hydrocarbon radical of from 2 to 5 carbon atoms, R is a lower alkyl group, R represents hydrogen or lower alkyl and A is a member of the group: consisting of saturated and unsaturated aliphatic hydrocarbon groups and hydroxyalkyl groups including ethers and esters of the hydroxy group. Typical examples ,ofthe group represented by R are methyl, ethyland. propyl, Representative of A are groups such as methyl, ethyl, allyl, propargyl, butenyl, Z-hydroxyethyl, 3-hydroxypropyl,

. Patented May 23,

patient,'it has been found thatithe preferred compounds of our invention are effective in doses ranging upwards from 150 mg. daily, the average daily clinical dose being 200 to 250 mg depending upon the syndrome. 1 For the am, .bulatory patient showing mild anxiety or low-grade;;tension, the effective doses are in a range of 10 to 2505mg. daily, the average dose being about 20 to 50mg. Forthe control of emesis, the compounds of this invention exert a depressant effect at doses of 10 to 15 mg. daily.

It has been found that, unlike most of the neuropsychiatric drugs in clinical use, the preferred compounds show few untoward side effects such as dry mouth, mydriasis, fall in blood pressure, and tachycardia. By virtue of the lowered incidencejof these side effects, the compounds of the invention can be used with relative safety in fcon-I junction with barbiturates for preoperativernedication for! reduction of anxiety.

Since for the most part, the compounds of the general formula are insoluble in aqueous media, they are preferably compounded in the form of soluble non-toxic acid addition salts such as the dihydrochloride, dimaleate, ditartrate, dicitrate and the like. The compoundsare preferably administered orally in tablets or elixirs in conjunction with suitable carriers and other types of oral pharmaceuticaldosage units. Where parenteral administra 3 tion is indicated, the compounds in the form of'non-toxic 2-(2-hydroxyethoxy)-ethyl, 2-acetoxyethyl, 2 -carbamoyl ethyl and the like. Included the group Y are ethylene, propylene, isopropylene, butylene and the like. I

We have found that the compounds of the general. formula possess certain important physiological properties which are usefulin chemopsychotherapeutic applications. These compounds manifest themselves by exerting a calming and a quieting effect, thereby lending themselves to application to neuropsychiatric patients in particular. 7

Thus, in their ability to calm mentally disturbed patients,

the restlessness and hyperactivity of the patient are re-. "1

lieved, permitting an improvement in appetite and sleep ing habits. Furthermore, these compounds are useful in allaying anxiety and tension which arise from a myriad of sources, such as gynecologic disorders, dermatologic conditions, environmental pressure, premenstrual tension, dysmenorrhea, and menopause. I

In addition, the compounds of our invention may be administered as anti-emetics in the treatment of nausea and vomiting. The mechanism by which this action occurs is not completely known, but we believe that the compounds exert a depressant effect on the centralnervous system and on the medulla, thus inhibiting the vomiting center and preventing or stopping emesis.

The foregoing central nervous system effects are particularly evident in the new compound of the general formula wherein A represents 2-hydroxyethyl and Y is a bivalent alkylene chain of 3 carbon atoms while increasing the number of carbon atoms in Y to 5 provides for compounds exhibiting useful antimicrobial properties.

For the schizophrenic or hyperactive neuropsychiatric acid addition salts are prepared in sterile solutions or sus-' pensions.

The compounds of our invention may be prepared by a number of alternate, but equivalent alkylation reactions. We prefer to employ the sequence of reactions set forth in the following equation:

' II III brnomon Nj; N at} V VI In the foregoing reaction, an acyl phenothiazine II ),efor, example ,2-acetylphenothiazine, is alkylated? with an: a'e;

propane :(III) whereby 'a' 2-acyl-l0-(ai-chloroa1kyl)phe-i nothiaz ine '(IV .is produced. 1 The reaction-is preferably? carried out in the presence of a basic condensing a'gentsuch; as the amides of sodium, potassium orlithiumin liquid ammonia or alkali metal carbonates in an inert solvent f stituent A-such'as 1 -,(2-hydroxyethyl)epiperazine; lmethai (2) CHaCH=CHC Cl 1 1 Alc. KOH

1 ZLIAIEI (2) 3,0:-

l (BCIH 7 (CH2); N] eon=orron= When carryingout the above reaction, it is necessary to protect the nuclear keto group in II by forming a ketal (VII) so as to avoid subsequent reduction of the ketone in later step. The ketal, VII, is condensed with a-bromow-chloroalkane in the presence of an agent such as sodamide, yielding the intermediate VIII. Reaction of VIII with an excess of carbethoxypiperazine yields the alkylation product IX. The carbethoxy group is hydrolyzed with alkali and the secondary amino group produced is rcacted'with an acid chloride, such as crotonyl chloride shown above. The amide, X, formed in the react-ion is reduced to the amine and the ketone regenerated by acid hydrolysis of the ketal. The above reaction is not limited to the preparation of compounds wherein A is unsaturated since the saturated fatty acid chlorides behave similarly. This reaction is particularly applicable to the preparation of compounds wherein A represents a 2- hydroxyethyl group; bromoethanol or ethylene oxide being employed in place of the acid chloride.

The foregoing equations all relate to the preparation of compounds of Formula I wherein a piperazine is alkylated with a phenothiazyl alkyl halide. Alternatively, the procedure whereby a 2-acylphenothiazine compound is alkylated with a piperazine alkyl halide or an equivalent thereof also results in the-formation of the compounds of Formula I.

II Y XII In this reaction, a 2-acylphenothiazine, II, is alkylated with an w-halogenated alkyl piperazine, XII; preferably in liquid ammonia solvent in the "presence of a basic condensing agent such as sodamide yielding I. Althoug'h the reactionzwould proceed without the use-of a catalyst, it is preferred to employ the condition specified inorderto 4 v obtain a more rapid reaction and higher yield. Specifi .cally, by adding a mole of Z-acetylphenothiazine to one equivalent of sodamide in liquid ammonia results in the formation of N-sodio-2-acetylphenothiazine. Alkylation of the sodio derivative in the usual manner with a pipera- VIII I a 0 t R N HunN N-cnlcn=cnona zinoalkyl halide, for example; -1-(2-ethoxyethyl)-4-(3'- chloropropyl) pipe'raz'ine, yields 1-(2-ethoxyethyl) -4- [3 (2- acetyl-l0-phenothiazy1')-propyl]piperazine, after work-up according to the above-describedprocedures. -In the equation compound XII is preferentially a chloride becauseofease of its preparation and handling, however, other functional alkylating groups such as bromo or tosyl may beused. r r i Compounds of Formula I wherein A represents a lower alkyl group which is further substituted by hydroxy, for example, 2-hydr'oxyethyl, may be transformed to ether and ester groupsby'relatively simple procedures. The following equation shows the conversion of XIII which contains a Z-hy'droxyethyl group to anether derivative, specifically, a compound containing a 2-ethoxy-ethyl group.

ll -CCH:V

V soon N cniomorm N cnlonlorr /S V a O, NaOCzHr ion a omorncnm N-oH,on,c1

xrv

o H \N CQH;

( HmN uotnomomn,

[Xv H is obtained the corresponding hydroxyalkoxy derivatives Ester derivatives are prepared in conventional manner, specific illustrations of which are set forth in the following examples.

EXAMPLE 1 1 -dllyl-4- [3-(2-acetyl-1 O-phenothiazyl -prpyl piperazine The requisite intermediate, 10-(3-chloropropyl) -2- acetylphenothiazine is prepared as follows:

T o a suspension of sodamide (from 3 grams of sodium) in 300 ml. of liquid ammonia is added 30 grams of 2- acetylphenothiazine. After stirring for one hour, there is added 19 grams of l-bromo-3-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml. of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue consists of crude 10-(3-chloropropyl)-2-acetylphenothia zine as a viscous oil and is used in the next step without further purification.

A mixture of 15 grams of l-allylpiperazine and 15 grams of crude 10-(3-chloropropyl)-2-acetylphenothiazine is heated on a steam bath for 18 hours. The mixture'is diluted with 200 ml. of water and extracted with ether. The ether solution is extracted with dilute hydrochloric acid. The aqueous acid solution is made alkaline with sodium hydroxide and the oil which separates is extracted with ether. The ether extracts are dried and concentrated to a residue consisting of the free base of this example. I

The crude base is purified by mixing same with maleic acid in ethyl acetate, filtering the precipitated salt and recrystallizing from ethanol yielding the dimaleate salt, M.P. 187.5-189.

By substituting 1-bromo-4-chlorobutane for the lbromo-3-chloropropane in the preparation of the intermediate, there is ultimately obtained by analogous reaction, 1-allyl-4-[4-(2 acetyl-10 phenothiazyl) butyl] -piperazine which is purified by conversion to its dimaleate salt according to the analogous procedures heretofore de-. scribed.

Alternatively, the compound of this example may be prepared according to the following method:

The requisite intermediate 1- a1lyl4-(3 ehloropropyl)- piperazine is prepared as follows 2" A mixture of 30 g. of l-allylpiperazine and 10 g. of 3-chloropropanol is stirred and heated on a steam bath for 8 hours. The mixture is diluted with water, saturated with potassium carbonate and extracted with ether. 'The ether extracts are dried over anhydrous potassium carbonate, concentrated and the residue distilled, yielding the intermediate 1-allyl-4-(3-hydroxypropyl)-piperazine, B.P. 120124/3 mm.

To a solution of 20 g. of the vpiperazino alkanol obtained above in 200 ml. of anhydrous benzene is added 15 g. of thionyl chloride, maintaining the reaction temperature below 10 during the addition. The reaction mixture is refluxed for four hours, cooled and the piperazino hydrochloride so formed is filtered rapidly and washed with benzene. The chloride salt is suspended in 150 ml. of anhydrous toluene. Into the cooled mixture is bubbled anhydrous ammonia gas whereupon ammonium chloride separates and is removed by filtration. The toluene solution of 1-ally1-4-(3-ch1oropropyl)-piperazine is used in later steps.

Z-acetyl phenothiazine is ketalized as follows: To a solution of 0.35 mole of Z-acetyl phenothiazine and 0.5 mole of ethyl orthoformate in 770 ml. of anhydrous ethanol is added 0.5 ml. of cencentrated hydrochloric acid. The mixture is allowed to stand overnight and then made alkaline with sodium ethoxidesolution. The sodium chloride is removed by filtration and the solution c'oncen-j trated to a residue in vacuo. The residue consisting of crude 2-acetyl phenothiazine diethylketal is added to a suspension of 'sodamide (from 2.5 g. of sodium) in 200 ml. of anhydrous toluene." After stirring and refluxing for one hour, the mixture is cooled and the toluene solu-f tion of 1-allyl-4-(3-chloropropyl)-piperazine' is added dropwise; The reaction mixture is refluxed and stirred for 8 hours and finally diluted with water. The organic layer. is separated and extracted with 200 ml. of 48% hyrobromic acid. The acid layer is separated,.refluxed for six hours, cooled and made alkaline with sodium hydroxide solution. The alkaline solution is extracted with ether and the ether layer is dried and concentrated yielding the free base of this example. 7

EXAMPLEZ 1-(2-hydr0xyethyl)4-[3-(2-acetyl-10-phen0thiazyl)- g propyl]-piperwzine The crude base obtained from the reaction of LID-( 3- chloropropyl) 2-acetylphenothiazine with. 1-( Z-hydroxyethyl) piperazine according to the procedure of Example 1,

is purified by conversion to its dimaleate salt, M.P.

1 67-168.5 from ethanol.

EXAMPLE 3 The intermediate 2-propionyl-l0-(3-chloropropyl) phenothiazine is prepared by reacting 2-propionylpheno-' heated at 40-50 C. for 5 hours. The alcohol is re-' moved by distillation and one liter of water is added. The

mixture is saturated with potassium carbonate, extracted with ether and the ether extracts being dried and concen trated. The residue'obtained from the ether solution-is.

refluxed with 500 ml. of concentrated hydrochloric acid for 40 hours. The resultant solution is concentrated to dryness, the residuedissolved in water, the aqueous solu-' tion saturated with potassium carbonate and thoroughly: extracted with ether. The ether extracts are dried, con-' centrated and the residue obtained therefrom is distilled, yielding 1-(2-methylallyl)-piperazine; B.P. l15l18/ A mixture of 31 g. of 10-(3 chloropropyl)-2-propionylphenothiazine and 28 g. of 1-(2-methylallyl) piperazine are stirred and heated ona steam bath for 18 hours. 7 The reaction mixture'is processed according to the analogous procedure of Example 1, yielding the free base of this example as the dimaleate salt.

EXAMPLE 4 e I-(Z-hydroxye'thyl)-4-[3-(Z-propionyl-IO-phendthiazyl)- propyl] -piperazine From 10 (3-chloropropyl)-2-propionylphenothiazine and 1-(2-hydroxyethyl)piperazine according to the pro cedure of Example 1, the crude base is purified by.con--, version to the dimaleate salt, M.P. -167" from;

g EXAMPLE f1 methyl-4 [3- (2-6lCetYl-1 O-pherioth iazyl -propyl] -p i per- J 1. azme By substituting an equivalent quantity of 1-methylpiperazine for the allylpiperazine in Example 1, the free base of this example is obtained.

L The base is purified by conversion to its dihydrochloride asfollows:

A solution of g. of the free base in 100 ml. of absolute ethanol is treated with a saturated solution of hydrogenchloride in anhydrous ethanol. Upon the addition of 100 ml. of anhydrous ether, the dihydrochloride is obtained, M. P. 254-2S5 after recrystallization from ethanol.

- EXAMPLE 6 7 1 -p'r0pargyl-4-[3-(2-acetyl-1 0-phen0thiazyl) -propyl] piperazine The requisite'intermediate l-propargylpiperazine is prepared as follows: A solution of 86 g. of anhydrous piperazine, 60 g. of propargyl bromide and 60 ml. of absolute ethanol is refluxed for 20-hours. The solvent is removed in vacuo, the residue is dissolved in 200 ml. of water and the solution so formed is saturated with solid potassium carbonate. The resultant mixture is extracted with ether and the extracts are dried and distilled collecting the fracion.; -B.P at 8290/7.0 mm. The substituted piperazinefso obtained crystallizes in the receiver; M.P. 53 5.4";

' A mixture of 17.5 g. of l-propargylpiperazine, 34 g. of 10-(3-chloropropyl)-2-acetylphenothiazine and 14 g. of anhydrous sodium carbonate is stirred and heated on a steam bath for 20 hours. The mixture is diluted with waterand the oil' which separates is extracted with ether. The combined ether extracts are extracted with dilute hydrochloric acid. The acid extracts are made alkaline with sodium hydroxide solution and extracted with ether. The ether extracts are dried and concentrated and the residue is converted to the dihydrochloride salt.

EXAMPLE 7 1 1-(3-methyl-2-butenyl) -4-[3-(2-propi0nyl-1O-phenothiazyZ)-propyl]-piperazine EXAMPLE 8 1- (Z-butenyl) -4- [3- (Z-acetyl-IO-phenothiazyl) -propyl] piperazine The requisite intermediate, l-(2-butenyl) -piperazine is prepared by reacting excess piperazine with crotonyl chloride in benzene solvent. The mixture is refluxed, cooled and extracted with dilute sodium carbonate solution. The benzene layer is dried and concentrated and the residue distilled in vacuo, yielding 1-crotonyl piperazine, B.P. 125l30/l mm.

A solution of the crotonyl derivative obtained above in anhydrous ether is added to a suspension of lithium aluminum hydride in anhydrous ether. The reaction mixture is stirred and refluxed for 10 hours and the excess hydride is destroyed by adding a minimum quantity of water, The lithium and aluminum hydroxides so stormed are removed by filtration and the ethersolution is concentrated to a residue which is purified by distilla- 8 tion; B.P. 120/l mm, yielding -1-(2-butenyl)piperazine. Reactionof the piper'azine so obtained with Z-acetyl-IO- phenothiazyl propyl chloride as' described in Example 1 yields the free base of this example which is purified by conversion to its dimaleate salt.

In the foregoing illustration, by starting with an equivalent quantity of 2-methylpiperazine or 2,5-dimethylpiperazine, there is ultimately obtained l-(2-butenyl)-4- [3-(2-acetyl-lO-phenothiazyl)-propyl]-2(or 3) methylpiperazine or 1 (2 buteny1)-4-[3-(2acetylrlO-phenothiazyl)-propyl]-2,5-dimethy1piperazine. The position of the methyl group in the mono methyl piperazinehas not been determined.

EXAMPLE, 9

1-(2-hydr0xyethoxyethyU-4- [3-(2-acetyl-10-pheno- 1 thiazyl) propyl] -piperazine -1-(2 chloroethyl)-4-[3 (10 phenothiazyl)propyl] piperazine is pr'eparedby adding to a solution of 21 g. of 1-(2-hydroxyethyl)-4-[3-(2-acetyl 10 phenothiazyl) prOpylJpiperaZine (from Example 3) in 250 ml. of anhydrous benzene'a solution of 9 g. of purified thionyl chloride in 25 ml. of benzene While cooling in an ice bath. The mixture is stirred at room temperature for three hours and made basic with dilute soduim hydroxide solution, keeping 'the temperature below 5. The benzene layer is separated, the aqueouslayer extracted with ether, the benzene 'and'ether layers thencombined, driedv over sodium sulfate, filtered and-concentrated in vacuo. The material is sufficiently pure for use in the following reaction. Q

The crude 1- (2-chloroethyl) -4- 3- 2 acetyl l O-phenothiazyl)propyl]piperazine in 50 ml. of anhydrous benzene is added to a stirred solution of 1.15 g. of sodium in 80 g. of ethylene glycol. The reaction mixture is heated on a steam bath for two hours, allowing the benzene to dis till, and thenstirred for 18 hours at room temperature. The reaction mixture is treated with ml. of water, extracted with benzene and the benzene layer extracted with dilute hydrochloric acid. The acid layer is made basic with dilute sodium hydroxide, the resulting oil extracted with ether and benzene, and the combined ether and benzene layers dried and concentrated. The crude oil is dissolved in ethyl acetate, and to it is added an excess of maleic acid in ethyl acetate. The dimaleate crystallizes as a white solid and is purified by recrystallization fromethanol.

Alternatively 1 (2-hydroxy-ethoxyethyl) -piperazine may be reacted with 3-(2-acetyl-10=phenothiazyl) propyl chloride according to procedures described heretofore, yielding the compound of this example.

' EXAMPLE 10 p 1 (Z-hydroxyethyl -4- 2- (2-acetyl-1 0-phen'0thiazyl) ethyl] -piperazine The requisite intermediate, 2 (2 acetyl-lO-phenothiazyD-ethyl chloride is prepared from Z-acetylphenothiazine and 2-chloro-ethyl p-toluenesulfonate in liquid ammonia using sodamide as condensing agent according to the analogous procedure of Example 1. 4

The crude chloroethyl intermediate is reacted with an excess of 1 (2 hydroxyethyl) piperazine according to methods heretofore described yielding the free base of this example.

EXAMPLE 1 1 1 -(4-hydroxybutyl) -4- [3-(2-acetyl-1 0-phenothiazyl propyl] piperazine ample 1.. The crude product of this example is purified. as the 'dihydrochloride salt by treatment with ethanolic hydrogen chloride.

EXAMPLE 12 l -(2 -hydrxyethyl -4- [3 (Z-acetyl-l 0 -phenothiazyl V propyl] -2,S-dimethylflperazine a EXAMPLE 13 1 -(2-acet0xyethyl -4- [3- (Z-acetyl-I O-phenothiazyl) propy l piperazine J A mixture of 10 g. of the base ofExample 2, 50 ml. of acetic anhydride and 5 g. of powdered sodium acetate is heated with stirring 'for 16 hours on a steam bath. The mixture is poured into 500ml. of ice water, made alkaline with sodium bicarbonate and the oil which separates is extracted with ether. The ether extracts are dried, concentrated and the residue consisting of the free base of this example-is converted to its dihydrochloride. Y In the above procedure, using propionic anhydride and sodium propionate, the analogous propionyl ester is obtained. Similarly, butyric anhydride and sodium butyratea'tfords the butyryl ester.

" EXAMPLE l4 1-(2-ethoxycarb0xyethyl)-4-[3-(2-acetyl-10-phen0- thiazyl)propyl]piperazine A mixture of 1.3 g. of powdered sodium, 20 g. of the base of Example 2 and 150 ml. of toluene is refluxed for two hours. The reaction mixture is cooled in an ice bath and 7 g. of ethyl chlorocarbonate is added dropwise. The mixture is refluxed and stirred for 6 hours, cooled and diluted with water. The toluene layer is separated, dried and concentrated. The crude residue is convetted/to its di naleate in ethyl acetate. 1 EXAMPLE 15 I (2-din2ethylcarbamoylethyl) -4-[3-(2-acetyl-10-pl 1en0- i thiazyD-propyl]-pipemzine V substituting dimethylcarbamoylchloride for ethyl chlorocarbonate inj Example 14, the free base of this example is obtained. 1

' EXAMPLE 16' 1-(2-hydroxypr0pyl)-4-[3-(Z-propionyl-IO-phenothiazyl)- pr0pyl1-piperazine To a suspension of sodamide (from 2.5 g. of sodium) in 300 ml. of liquid ammonia there is added 24 g. of 2- propionyl-phenothiazine. After stirring for ten minutes, 18 g. of l-bromo-3-chloropropane is added dropwise and ,theeammonia is allowed'to evaporate. The reaction.

mixture is decomposed with water, the oil extractedwith ether, dried and concentrated. The crude -(3-chlo'ropropyl)-2-propionylphenothiazine is heated with 35 g. of l-carbethoxypiperazine on a steam bath for sixteen hours. The mixture is decomposed withwater, the oil extracted with'ether, dried and concentrated. The crude l carbethoxy 4 [3-(2-propionyl-l0-phenothiazyl) propyl]piperazine so obtained is dissolved in 600 ml. of absolute ethanol containing 30 g. of potassium hydroxide andrefluxed 'for 16 hours. The ethanol is removed .in vacuo, the residue treated with Water and the oil extracted with ether; the ether solution is dried and concentrated to a residue.

'A solution of '37 g. of crude 4-[3-(2-propionyl 10- phenothiazyl)propyl]piperazine obtained above in' 200 ml. of methanol is treated with 20 g. of propylene oxide with cooling. After refluxing for six hours, the methanol is removed in vacuo, the residue treated with water and the oil extracted with ether and dried. Concentration of 10 the ethereal extractsyieldsthecompound of this ex= pl A EXAMPLE 17 I 1-ethyl-4 [3- (Z-acetyl-Io-phenothidzyl)-propyl] piperazine 3 v i From the reaction of l-ethyl piperazine and 10-(3- chloropropyl)-2-'acetylphenothiazine according to the procedure of- Example l-yields the free base of this example.

Similarly,.1-propyl piperazine yields the ing l-propylanalog of this example. i I a i :Substituting 2-propionylphenothiazine intheforegoingprocedures yields the analogous phenothiazine compound containing the propionyl substituent at carbon 2;

EXAMPLE 1s correspond 1 -(2 -hydro2 cyethyl -4-[4-(2-acetyl-1 O-phenothiazyD- butyl]-piperazine.

' The requisite intermediate, ;10(4-chlorobutyl)-2- acetylphenothiazine is prepared according to the analogous procedulre of Examplel by substituting 1-bromo-' 4-chlorobutane for 1-bromo-3-chloropropane.-

Condensation of the butyl intermediate obtained above with' I-(Z-hydroxyethyl) piperazine yields the free base of this example. i

w EXAMPLE 19 '1 2{hydroxyethyl)-4[3-(2-butyryl-1O-phenothiazyl) prawn-piperazine H The requisite'interm'ediate, 2-butyryl phenothiazine is prepared as follows: 1 r

To a stirredand cooled mixtur'eof 93 g. of l0-acetyl-- phen othiazi ne,.205 g. powdered aluminum chloride and 1350 ml. of carbon disulfide is added, dropwise, 67 g. of butyric anhydride. The mixture is stirred and refluxed for seven hours, cooled and the carbon .disulfide removed by decantatiqn. The residue is treated'with ice' and concentrated hydrochloric acid and extracted with ether...."lheether layer is.washed with dilute acid, water and sodium carbonate solution in turn. The ether solution is dried and concentrated to a residue consisting of Z-butyryl-lO- acetylphenothiazine. Hydrolysis is effected by refluxing the residue with 33 g. of potassium hydroxide in 400 ml. of absolute ethanol for one hour. Upon cooling, 2-butyryl phenothiazine crystallizes as bright orange crystals and is purified by recrystallization from ethyl acetate.

Reaction of 2-butyryl phenothiazine with 1-brorno-3- chloropropane a'nd subsequently with l-(2-hydroxyethyl) piperazine as described in Example 1 'yields'the compound of this example. J 7

EXAMPLE 20 1- (2-carbam0yl ethyl) -4- [3- (Z-acetyI-IO-phenothiazyl) propyl] piperazine To a stirred solution of 41 g. of the compound of Example 2 in ml. of dry pyridine, there is added dropwise 17.2 g. of phenyl chlorocarbonatekeeping the temperature between 25-30". The reaction mixture is stirred for sixteen hours, diluted with Water and the oil extracted with chloroform. The chloroform extracts are washed this example is purified by recrystallization and conversion to the dihydrochloride salt.

The requisite intermediate, 3-(2-acetyl-l0-phenothiazyl)-2-propanol is prepared as follows: Toa suspension of sodamide (from 4.6 g. of sodium) and 200 ml.'of toluene, there is added 48.2 g; of 2-acetylphenothiazine. The mixture is stirred and refluxed for three hours, cooled to 60. and 23.2 g. of 1,2-oxidopropane is added dropwise. The reaction mixture is stirred and refluxed fortwo hours, cooled and decomposed with water. The toluene layer is separated, concentrated in vacuo and the residual oil fractionated, collecting the fraction'b'oiling at 210-220/ 0.5 mm.

Replacement of the hydroxyl group is effected by adding dropwise 50 g. of phosphorous tribromide to a solu-' tion of 29 g. of the isopropanol intermediate obtained abovein 60 ml. of chloroform. The resultant yellow solution is refluxed for three hours during which time a yellowish oil separates. The mixture is cooled and stirred with sodium bisulfite and the orange mixture is filtered. The filtrate is dried over calcium chloride, filtered and concentrated to a residue in vacuo. The residue is dissolved in chloroform and washed with sodium bisulfite solution. The sodium bisulfiteis extracted with chloroform and the combined chloroform extracts are 'dried over calcium chloride and concentrated in vacuo to a residue consisting of the crude bromo intermediate.

The crude bromide is condensed with 1-(2-hydroxyethyl)-piperazine according to the procedure of Example 1, yielding the compound of this example.

i We claim:

1. 1-(2-hydroxyethyl) 4 [3-(2-acetyl-10-phenothiazyl) -propyl] -pip erazine.

2. 1 -propargyl-4-[3-(2-acetyl phenothiazyD-propyll-piperazine.

3. 1-(2-hydroxyethyl)-4-[3-(2 propionyl 10 phenothiazyl)-propyl]-piperazine.

' 4. 1-methy1-4-[3-(2-acetyl10-phenothiazy1) propyl] piperazine.

5. A compound of the structural formula:

wherein A and R arelower alkyl groups.

7 6. A'compound of the structural formula:

where R is a lower alkyl group and A is a lower alkylene radical bearing a hydroxy substituent, said lower alkylene radical having at'1east2 carbon atoms separating the l-piperazinyl-nitrogen atom from said hydroxy substituent.

V 12 wherein R is a lower alkyl group and A is a lower alkenyl group,

8. 1-(2-carbamoylethyD-4 [3-(2-acetyl 10 phenothiazyl)-propyl]piperazine.

'9. A compound selected from the group consisting of phenothiazyl alkyl piperazines of the structural formula:

and the non toxic acid addition salts thereof wherein R' is a lower alkyl group, R is a member of the group consisting of hydrogen and lower alkyl, Y is a bivalentsaturated aliphatic hydrocarbon group having from 2 to 5 carbon atoms with at least 2 carbon atoms separating the 10-phenothiazyl-nitrogen atom from the 4-piperazinyl nitrogen atom, and A is a member of the group consisting of lower alkyl, lower 'alkenyl, lower alkynyl, and a substituted lower alkyl of the group consisting of hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, carbamoyloxy-lower alkyl, di-lower alkyl. carbamoyloxylower alkyl, lower alkoxy-lower 'alkyl and hydroxy lower alkoxy-lower alkyl, wherein the substituent is separated from the l-piperazinyl nitrogen atom by at least 2 carbon atoms.

10. A compound of the structural formula:

- 10 phenothiawherein is a lower alkyl group and A is a lower alkynyl group.

A References Cited'in the fileof this patent UNITED STATES PATENTS 2,766,235 Cusic Oct. 9, 1956 FOREIGN PATENTS 293/55 South Africa Aug. 22, 1955 535,922 Belgium Mar. 15, 1955 537,689 Belgium Oct. 26, 1955 OTHER REFERENCES Bergmann: The-Chemistry of Acetylene and Related Compounds, page '80, Interscience Publishers, Inc., N.Y., 1948. 

9. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PHENOTHIAZYL ALKYL PIPERAZINES OF THE STRUCTURAL FORMULA: AND THE NON TOXIC ACID ADDITION SALTS THEREOF WHEREIN R IS A LOWER ALKYL GROUP, R1 IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL, Y IS A BIVALENT SATURATED ALIPHATIC HYDROCARBON GROUP HAVING FROM 2 TO 5 CARBON ATOMS WITH AT LEAST 2 CARBON ATOMS SEPARATING THE 10-PHENOTHIAZYL-NITROGEN ATOM FROM THE 4-PIPERAZINYL NITROGEN ATOM, AND A IS A MEMBER OF THE GROUP CONSISING OF LOWER ALKYL, LOWER ALKENYL, LOWER ALKYNYL, AND A SUBSTITUTED LOWER ALKYL OF THE GROUP CONSISTING OF HYDROXY-LOWER ALKYL, LOWER ALKANOLOXY-LOWR ALKYL, CARBAMOYLOXY-LOWER ALKYL, DI-LOWER ALKYL CARBAMOYLOXYLOWER ALKYL, LOWER ALKYL AND HYDROXY LOWER ALKOXY-LOWER ALKYL, WHEREIN THE SUBSTITUENT IS SEPARATED FROM THE 1-PIPERAZINYL NITROGEN ATOM BY AT LEAST 2 CARBON ATOMS. 